Review BRAF inhibition and the spectrum of granulomatous reactions

The B-Raf proto-oncogene serine/threonine kinase (BRAF) gene is the most frequently mutated gene in malignant melanoma (MM) and papillary thyroid cancer (PTC) and is causally involved in malignant cell transformation. Mutated BRAF is associated with an aggressive disease phenotype, thus making it a top candidate for targeted treatment strategies in MM and PTC. We show that BRAF mutations in both MM and PTC drive increased expression of oncomiR-3151, which is coactivated by the SP1/NF-κB complex. Knockdown of microRNA-3151 (miR-3151) with short hairpin RNAs reduces cell proliferation and increases apoptosis of MM and PTC cells. Using a targeted RNA sequencing approach, we mechanistically determined that miR-3151 directly targets TP53 and other members of the TP53 pathway. Reducing miR-3151’s abundance increases TP53’s mRNA and protein expression and favors its nuclear localization. Consequently, knockdown of miR-3151 also leads to caspase-3–dependent apoptosis. Simultaneous inhibition of aberrantly activated BRAF and knockdown of miR-3151 potentiates the effects of sole BRAF inhibition with the BRAF inhibitor vemurafenib and may provide a novel targeted therapeutic approach in BRAF-mutated MM and PTC patients. In conclusion, we identify miR-3151 as a previously unidentified player in MM and PTC pathogenesis, which is driven by BRAF-dependent and BRAF-independent mechanisms. Characterization of TP53 as a downstream effector of miR-3151 provides evidence for a causal link between BRAF mutations and TP53 inactivation.

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PDCT-08. SUPERIOR OUTCOME FOR BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION

Neuro-Oncology ◽

10.1093/neuonc/noz175.771 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi184-vi185

Author(s):

Liana Nobre ◽

Michal Zapotocky ◽

Vijay Ramaswamy ◽

Scott Ryall ◽

Julie Bennett ◽

...

Keyword(s):

Median Time ◽

Objective Response ◽

Progression Free Survival ◽

Homozygous Deletion ◽

Braf V600e ◽

Low Grade ◽

Rapid Responses ◽

Braf Inhibition

Abstract BACKGROUND Children with pediatric low grade glioma’s (PLGG) harboring BRAF V600E mutation have poor outcome due to relative resistance to chemo-radiation and higher risk of malignant transformation. However, the role of targeted BRAF inhibition in these tumors is poorly defined. METHODS We assembled an international cohort of children with BRAF V600E mutant gliomas treated with BRAF inhibition, from 29 centers participating in the PLGG taskforce, and collected response, survival and molecular parameters. RESULTS Sixty-seven patients were treated with BRAFi (56 PLGG and 11 high grade gliomas) for a median time of 17.4 months (6 – 61 months), with 13 PLGG treated upfront. Objective responses was observed in 80% of PLGG patients compared to 28% with conventional chemotherapy (p< 0.001). Rapid responses were observed in most PLGG patients (median of 4 months), sustained in 86% of tumors up to 5 years while on therapy. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. Seventeen patients with PLGG discontinued BRAFi and 76.5% (13/17) progressed rapidly after discontinuation (median time 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies such as concomitant homozygous deletion of CDKN2A or H3K27M mutation were not associated with lack of response to BRAFi. Overall these responses translated to 2-year progression-free survival of 0.636 (95%CI 0.505–0.802) and 0.43 (95% CI 0.32–0.57) for BRAFi and chemotherapy treated BRAF V600E PLGG respectively (p=0.003). CONCLUSION The use of BRAFi results in objective, robust and durable responses in BRAF V600E PLGG and is associated with favorable survival. Larger prospective studies will be required to determine appropriate regiments, and long-term functional outcomes with BRAFi therapy in childhood gliomas.

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BRAF inhibition curtails IFN‐gamma‐inducible PD‐L1 expression and upregulates the immunoregulatory protein galectin‐1 in melanoma cells

Molecular Oncology ◽

10.1002/1878-0261.12695 ◽

2020 ◽

Vol 14 (8) ◽

pp. 1817-1832 ◽

Cited By ~ 3

Author(s):

Patryk Górniak ◽

Maja Wasylecka‐Juszczyńska ◽

Iwona Ługowska ◽

Piotr Rutkowski ◽

Anna Polak ◽

...

Keyword(s):

Melanoma Cells ◽

Ifn Gamma ◽

Braf Inhibition

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Preoperative BRAF inhibition in patients with irresectable locally advanced stage III melanoma

Melanoma Management ◽

10.2217/mmt-2018-0002 ◽

2018 ◽

Vol 5 (2) ◽

pp. MMT08

Author(s):

Marloes Faut ◽

Mathilde Jalving ◽

Gilles F Diercks ◽

Geke A Hospers ◽

Barbara L van Leeuwen ◽

...

Keyword(s):

Locally Advanced ◽

Stage Iii ◽

Advanced Stage ◽

Braf Inhibition ◽

Stage Iii Melanoma

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Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition

JCO Precision Oncology ◽

10.1200/po.19.00298 ◽

2020 ◽

pp. 561-571 ◽

Cited By ~ 4

Author(s):

Liana Nobre ◽

Michal Zapotocky ◽

Vijay Ramaswamy ◽

Scott Ryall ◽

Julie Bennett ◽

...

Keyword(s):

Objective Response ◽

Braf Inhibitor ◽

Progression Free Survival ◽

Homozygous Deletion ◽

Braf V600e ◽

Rapid Progression ◽

Low Grade ◽

Term Survival ◽

Braf Inhibition ◽

Poor Outcomes

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

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